Topical instillation has been the most common method of administration for ophthalmic medications since ocular treatments have existed. That is why it would be expected to be simple, practical and efficient.
Even though there is normally a certain number of patients who can administer their medications themselves, studies on the observance of medicinal directions show that a large number of them do not succeed in doing this. The necessity in ambulatory medicine of relying on the patient to carry out correct treatment is a factor in the non-compliance with doctors' directions and more particularly when the treatment is as difficult as in ophthalmology.
The impossibility of a patient positioning the end of the normal droppers without a mirror, or without corrective lenses when the latter are necessary for looking at oneself in a mirror, is very dangerous. There is a high risk of damaging the cornea together with a risk of contamination of the active constituent of the medication if the end of the dropper comes into contact with the conjunctiva as in the majority of cases.
Furthermore, when a drop is administered to the eye successfully despite the above difficulties, a significant loss of medication occurs by overflowing onto the face and by draining into the naso-lachrymal canal.
The distribution of the active substance in the general circulation essentially occurs by the intermediary of the naso-lachrymal canal. Its presence in the systemic circulation contributes to the appearance of serious general secondary effects following a simple ocular instillation and this has generated considerable interest in the design of various systems for the administration of active constituents which could minimize the risk of systemic toxicity.
If the liquid is trapped in the folds of the conjunctiva is included, the normal volume of tears in the eye is about 10 ml. A total volume of liquid of about 20 ml can be retained for a short time, if the eyelids are not closed again after the administration of the topical medication. When a single drop of medication is applied to the eye, normally having a volume of 30 to 60 ml, the major portion of the administered drop runs over the cheeks whilst the naso-lachrymal drainage system rapidly drains off the excess volume.
Thus, increasing the size of the drops does not increase the bioavailability. According to some authors, only 5% of the total quantity of the active ingredients in fact reach the aqueous humour.
On the contrary, the large size of the drops causes an exacerbation of corneal sensitivity which itself causes two synergic defence reflexes: the blinking of the eyes and lachrymation, the combination of these two resulting in the elimination of the major portion of the ophthalmic drop.
However, systemic absorption is proportional to the size of the drop, given that the subsequent drainage through the naso-lachrymal canal usually leads to the active constituent being absorbed into the plasma through the nasal mucosa or even to being swallowed.
When, in ophthalmology, active constituents are used which have potential systemic secondary effects, such as beta-blockers, it is important to try to limit the size of the drops in order to minimize the risk of secondary effects. For the purpose of reducing systemic absorption, it has been proposed for example to compress the nasal end of the lower eyelid for five minutes after the instillation in order to cause the occlusion of the lachrymal point. That is why it would be desirable to have a device designed to prevent systemic re-absorptions, that is to say to deliver a dose of the active product or products whose volume does not exceed the 25 ml maximum volume available in the conjunctival space.
Certain pathologies require, in a good number of cases, the combination of two active constituents. It would be desirable for the said device to be able to deliver, for example, two separate drops of 12.5 ml of two different liquids. A good number of active constituents used in ophthalmology are very difficult to combine into a single formulation. This is the case for example when it is desired to associate one hydrophilic active compound with a lipophilic active compound or two compounds with a different pH. Such a combination cannot be achieved in the same bottle without a major change in at least one formulation, leading to a significant reduction in its penetration or in its action. Furthermore, to administer two separate topical solutions results in excessive volumes and even more side effects while less active ingredient of the first drop is left as a result of the wash out by the second drop. This is especially true in ocular applications as well as for most of topical application.
This is the case, in ocular instillation for example, for a combination of dorzolamide (Trusopt) and epinephrine. The respective volumes of each of these two components administered is normally 30 ml for the former and 40 to 60 ml for the latter, which results in a minimum total volume of about 70 ml. Now, as mentioned above, the capacity of the eye is a maximum of 20 to 25 ml. That is why a combined formula of this association has been developed by the manufacturer, at the cost of major difficulties, an enormous budget and more than twelve years of development.
Furthermore, it would be desirable for the administration of the medication to take place in a part of the eye which is not very sensitive in order to avoid the reactions mentioned above. Such a low-sensitivity zone is the lower conjunctival cul-de-sac.
It would therefore be desirable to have an instillation device capable of simultaneously dispensing two separate active constituents and complying with the objectives and constraints defined above.
Such a device should preferably allow a patient to instill easily and concomitantly two separate drops of a medication by self-administration, in any environment whatsoever, whether this be at home, at work or elsewhere, without having to tilt the head backwards.
This device should be reliable and should eliminate the present risks of damaging the eye and of contaminating the contents.
Furthermore, the size of the drops thus administered should be small, so that the sum of the two drops administered does not exceed the maximum capacity of the eye, in order to control the dose of medication actually administered and to minimize the risk of systemic absorption with the potential toxicity which accompanies this.
In fields other than ophthalmology, certain pathologies also require, in a large number of cases, the association of two active ingredients. A large number of active ingredients, for example in Otorhinolaryngology, Pneumatology, Dermatology, Gynaecology, are very difficult to combine in a single formulation. This is the case for example, as mentioned above, when it is desired to associate a hydrophilic active compound with a lipophilic compound in a liquid phase when the two active compounds whose penetration and activity pH figures differ from one another. Such a combination cannot be achieved in the same bottle without a significant change in at least one formulation, which leads to a significant reduction in its penetration or its efficacy.